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Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy.

ABSTRACT: Reparative macrophages play an important role in cardiac repair post-myocardial infarction (MI). Bone marrow mononuclear cells (BM-MNCs) have been investigated as a donor for cell therapy but with limited clinical success. These cells, however, may be utilized as a source for reparative macrophages. This translational study aimed to establish a robust in vitro protocol to produce functional reparative macrophages from BM-MNCs and to establish pre-clinical evidence of the efficacy of reparative macrophage transplantation for the treatment of MI. Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-?1 or combinations of these in vitro. The concomitant administration of M-CSF and IL-4 produced the highest rate and largest number of CD11b+F4/80+CD206+ reparative macrophages. Expression and secretion of tissue repair-related factors including IGF-1, TGF-?1, VEGF and IL1-ra were remarkably enhanced in reparative macrophages compared to BM-MNCs. These cells were transplanted in a mouse MI model, resulting in evident improvement in cardiac function recovery, compared to BM-MNC transplantation. Histological studies showed that reparative macrophage transplantation enhanced myocardial tissue repair including augmented microvascular formation, reduced cardiomyocyte hypertrophy and attenuated interstitial fibrosis. Moreover, survival of reparative macrophages in the heart post-transplantation was increased compared to BM-MNCs. Reparative macrophage transplantation also increased host-derived reparative macrophages in part through TGF-? secretion. In conclusion, concomitant M-CSF?+?IL-4 treatment effectively produced reparative macrophages from BM-MNCs in vitro. Transplantation of produced reparative macrophage achieved a superior therapeutic efficacy, compared to BM-MNC transplantation, through the enhanced quantity and quality of donor cell engraftment. Further development of this advanced cell-based therapy is warranted.

SUBMITTER: Podaru MN

PROVIDER: S-EPMC6675756 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy.

Podaru Mihai-Nicolae MN Fields Laura L Kainuma Satoshi S Ichihara Yuki Y Hussain Mohsin M Ito Tomoya T Kobayashi Kazuya K Mathur Anthony A D'Acquisto Fulvio F Lewis-McDougall Fiona F Suzuki Ken K

Basic research in cardiology 20190801 5

Reparative macrophages play an important role in cardiac repair post-myocardial infarction (MI). Bone marrow mononuclear cells (BM-MNCs) have been investigated as a donor for cell therapy but with limited clinical success. These cells, however, may be utilized as a source for reparative macrophages. This translational study aimed to establish a robust in vitro protocol to produce functional reparative macrophages from BM-MNCs and to establish pre-clinical evidence of the efficacy of reparative m ...[more]

PMID: 31372765

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Project description:BackgroundOwing to the multifactorial nature of the pathogenesis of diabetic peripheral neuropathy (DPN), conventional drug therapies have not been effective. The application of stem cells transplantation may be useful for the treatment of DPN. This study was designed to assess the safety and therapeutic effects of autologous bone marrow mononuclear cells (BMMNCs) transplantation on the treatment of refractory DPN.MethodsOne hundred and sixty-eight patients with refractory DPN were recruited and enrolled in the study. They received intramuscular injection of BMMNCs and followed at 1, 3, 6, 12, 18, 24, and 36 months after the transplantation. Clinical data, Toronto Clinical Scoring System (TCSS), and nerve conduction studies (NCSs) were compared before and after the transplantation.ResultsThe signs and symptoms of neuropathy were significantly improved after BMMNCs transplantation. The values of the TCSS scores at 1 month (9.68 ± 2.49 vs. 12.55 ± 2.19, P < 0.001) and 3 months (8.47 ± 2.39 vs. 12.55 ± 2.19, P < 0.001) after the treatment reduced significantly compared with the baseline value. This decrement remained persistent until the end of the study. The conduction velocity and action potential and sensory nerves were significantly improved after transplantation (3 and 12 months after the treatment vs. the baseline: motor nerve conduction velocity, 40.24 ± 2.80 and 41.00 ± 2.22 m/s vs. 38.21 ± 2.28 m/s, P < 0.001; sensory nerve conduction velocity, 36.96 ± 2.26 and 39.15 ± 2.61 m/s vs. 40.41 ± 2.22 m/s, P < 0.001; compound muscle action potential, 4.67 ± 1.05 and 5.50 ± 1.20 μV vs. 5.68 ± 1.08 μV, P < 0.001; sensory nerve action potential, 4.29 ± 0.99 and 5.14 ± 1.26 μV vs. 5.41 ± 1.14 μV, P < 0.001). No adverse event associated with the treatment was observed during the follow-up period.ConclusionsAutologous transplantation of BMMNCs may be an effective and promising therapeutic strategy for the treatment of refractory DPN.

Dataset Information

Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy.

Publications

Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy.

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